Coronary artery bypass grafting has been utilized as a beneficial treatment for myocardial ischemic disease for over three decades. Failure of coronary artery venous grafts occurs at a substantial rate and has a large impact on two main endpoints, survival and quality of life. An exhaustive amount of basic research has been generated to delineate possible mechanisms responsible for graft failure and modalities to prevent its occurrence. Although pharmacotherapy exists, insufficient translation has emerged from the bench to the operating room. In this article, we review the literature regarding the current mechanisms and mediators including growth factors, nitric oxide and genetics leading to saphenous vein graft occlusion. The review addresses the current state of affairs and modes for prevention of vein graft failure perioperatively and newer technologies that may help ameliorate this problem in the future.